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Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro- and antitumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarizing the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.

Surface science such as superhydrophobic and superoleophilic surfaces plays a sensitive function in a separating oil/water mixture as a result of increasing industrial oil and organic solvents drainage occurrence. In this work, copper hydroxide nanoneedles layer were synthesized onto Egyptian cotton fabrics (CF) treated with polydopamine, Ag nanoparticles (NPs) and Cu NPs via facile immersion process. Fourier transform infrared, X-ray diffraction and scanning electron microscope (SEM) were used to investigate the functionalized surface of CF with copper hydroxide layer. SEM images confirmed that the modified membranes were rougher compared with pure surface of CF. The contact angle measurement emphasized the hydrophobicity of the modified membranes and it was found that the water contact angle has a value of 168°. The absorption capacity of the modified CF membrane was 10.1 g g − 1 for diesel oil and the separation efficiency of this modified surface was higher than 99%. It was noted that the flux in the case of low viscosity solvent as n-hexane was 72,172.9 Lm− 2 h− 1, while for the viscous oil as diesel was 14,460.3 Lm− 2 h− 1.

Differences of Sex Development (DSD) comprise a variety of congenital conditions characterized by atypical chromosomal, gonadal, or anatomical sex. Diagnosis and monitoring of treatment of patients suspected of DSD conditions include clinical examination, measurement of peptide and steroid hormones, and genetic analysis. This position paper on peptide hormone analyses in the diagnosis and control of patients with DSD was jointly prepared by specialists in the field of DSD and/or peptide hormone analysis from the European Cooperation in Science and Technology (COST) Action DSDnet (BM1303) and the European Reference Network on rare Endocrine Conditions (Endo-ERN). The goal of this position paper on peptide hormone analysis was to establish laboratory guidelines that may contribute to improve optimal diagnosis and treatment control of DSD. The essential peptide hormones used in the management of patients with DSD conditions are follicle-stimulating hormone, luteinising hormone, anti-Müllerian hormone, and Inhibin B. In this context, the following position statements have been proposed: serum and plasma are the preferred matrices; the peptide hormones can all be measured by immunoassay, while use of LC-MS/MS technology has yet to be implemented in a diagnostic setting; sex- and age-related reference values are mandatory in the evaluation of these hormones; and except for Inhibin B, external quality assurance programs are widely available.

Oily water contamination has been sighted as one of the most global environmental pollution. Herein, copper hydroxide nanorods layer was constructed onto cellulosic filter paper surface cured with polydopamine, Ag nanoparticles, and Cu NPs through immersion method. This work has been aimed to produce a superhydrophobic and superoleophilic cellulosic filter paper. The structure, crystalline, and morphological properties of these modified cellulosic filter paper were investigated. Scanning electron microscope images confirmed that the modified surface was rougher compared with the pristine surface. The contact angle measurement confirmed the hydrophobic nature of these modified surfaces with a water contact angle of 169.7°. The absorption capacity was 8.2 g/g for diesel oil and the separation efficiency was higher than 99%. It was noted that the flux in the case of low viscosity solvent as n-hexane was 9663.5 Lm−2 h−1, while for the viscous oil as diesel was 1452.7 Lm−2 h−1.

In search for effective multi-targeting drug ligands (MTDLs) to address low-grade inflammatory changes of metabolic disorders, we rationally designed some novel glitazones-like compounds. This was achieved by incorporating prominent pharmacophoric motifs from previously reported COX-2, 15-LOX and PPARγ ligands. Challenging our design with pre-synthetic docking experiments on PPARγ showed encouraging results. In vitro tests have identified 4 compounds as simultaneous partial PPARγ agonist, potent COX-2 antagonist (nanomolar IC50 values) and moderate 15-LOX inhibitor (micromolar IC50 values). We envisioned such outcome as a prototypical balanced modulation of the 3 inflammatory targets. In vitro glucose uptake assay defined six compounds as insulin-sensitive and the other two as insulin-independent glucose uptake enhancers. Also, they were able to induce PPARγ nuclear translocation in immunohistochemical analysis. Their anti-inflammatory potential has been translated to effective inhibition of monocyte to macrophage differentiation, suppression of LPS-induced inflammatory cytokine production in macrophages, as well as significant in vivo anti-inflammatory activity. Ligand co-crystallized PPARγ X-ray of one of MTDLs has identified new clues that could serve as structural basis for its partial agonism. Docking of the most active compounds into COX-2 and 15-LOX active sites, pinpointed favorable binding patterns, similar to those of the co-crystallized ligands. Finally, in silico assessment of pharmacokinetics, physicochemical properties, drug-likeness and ligand efficiency indices was performed. Hence, we anticipate that the prominent biological profile of such series will rationalize relevant anti-inflammatory drug development endeavors.

Cancer is a multifactorial disorder involving multiplicity of interrelated signaling pathways and molecular targets. To that end, a multi-target design strategy was adopted to develop some 1,2,3-triazoles hybridized with some pharmacophoric anticancer fragments, as first-in-class simultaneous inhibitors of COX-2, 15-LOX and tumor associated carbonic anhydrase enzymes. Results revealed that compounds 5a, 5d, 8b and 8c were potent inhibitors of COX-2 and 15-LOX enzymes. COX-2 inhibitory activity was further demonstrated by the inhibition of the accumulation of 6-keto-PGF1α, a metabolite of COX-2 products in two cancer cell lines. The sulfonamide bearing derivatives 5d and 8c were effective nanomolar and submicromolar inhibitors of tumor associated hCA XII isoform, respectively. Strong to moderate inhibitory activities were observed in the in vitro antiproliferative assay on lung (A549), liver (HepG2) and breast (MCF7) cancer cell lines (IC50 2.37–28.5 μM) with high safety margins on WI-38 cells. A cytotoxic advantage of CA inhibition was observed as an increased activity against tumor cell lines expressing CA IX/XII. Further mechanistic clues for the anticancer activities of compound 5a and its sulfonamide analog 5d were derived from induction of cell cycle arrest at G2/M phase. They also triggered apoptosis via increasing expression levels of caspase-9 and Bax together with suppressing that of Bcl-2. The in vitro anti-tumor activity was reflected as reduced tumor size upon treatment with 8c in an in vivo cancer xenograft model. Docking experiments on the target enzymes supported their in vitro data and served as further molecular evidence. In silico calculations and ligand efficiency indices were promising. In light of these data, such series could offer new structural insights into the understanding and development of multi-target COX-2/15-LOX/hCA inhibitors for anticancer outcomes.

For the past three decades, pharmaceutical research has been mainly converging to novel carrier systems and nanoparticulate colloidal technologies for drug delivery, such as nanoparticles, nanospheres, vesicular systems, liposomes, or nanocapsules to impart novel functions and targeting abilities. Such technologies opened the gate towards more sophisticated and effective multi-acting platform(s) which can offer site-targeting, imaging, and treatment using a single multifunctional system. Unfortunately, such technologies faced major intrinsic hurdles including high cost, low stability profile, short shelf-life, and poor reproducibility across and within production batches leading to harsh bench-to-bedside transformation.Currently, pharmaceutical industry along with academic research is investing heavily in bioconjugate structures as an appealing and advantageous alternative to nanoparticulate delivery systems with all its flexible benefits when it comes to custom design and tailor grafting along with avoiding most of its shortcomings. Bioconjugation is a ubiquitous technique that finds a multitude of applications in different branches of life sciences, including drug and gene delivery applications, biological assays, imaging, and biosensing.Bioconjugation is simple, easy, and generally a one-step drug (active pharmaceutical ingredient) conjugation, using various smart biocompatible, bioreducible, or biodegradable linkers, to targeting agents, PEG layer, or another drug. In this chapter, the different types of bioconjugates, the techniques used throughout the course of their synthesis and characterization, as well as the well-established synthetic approaches used for their formulation are presented. In addition, some exemplary representatives are outlined with greater emphasis on the practical tips and tricks of the most prominent techniques such as click chemistry, carbodiimide coupling, and avidin-biotin system.

Background Magnetic resonance spectroscopy (MRS) is usually added to conventional magnetic resonance imaging (MRI) to refine the diagnosis of different brain lesions. Stereotactic brain biopsy is a well-established method to obtain tissues for histopathologic examination. The purpose of the study is to compare the diagnostic yields of MRS and stereotactic biopsy in the characterization of brain lesions. Material and Methods A prospective study conducted on 27 consecutive patients presenting with multifocal, diffuse, as well as deeply seated intra-axial brain lesions. All patients had both brain MRI and MRS prior to stereotactic biopsy. Histopathologic examinations of the obtained tissue specimens, using appropriate stains including immunostains, were performed. Results MRS diagnosed neoplastic brain lesions in 15 cases (56%) and nonneoplastic brain lesions in 12 (44%). Correlation between the preoperative diagnosis by MRS and the histopathologic diagnosis following stereotactic biopsy of either a neoplastic or nonneoplastic lesion revealed matching in 25 of 27 cases (sensitivity 88%; specificity 100%). Within the group of cases (n = 15) diagnosed preoperatively by MRS as neoplastic, 12 patients were diagnosed with brain gliomas of different grades. The MRS grading of gliomas exactly matched the histopathologic grading following stereotactic biopsy in 10 of the 12 cases (sensitivity 89%; specificity 67%). Conclusions MRS is a useful addition to the management armamentarium, providing molecular information that assists in the characterization of various brain lesions. Multivoxel MRS may increase the diagnostic yield of stereotactic biopsy by guidance to target the higher choline and lower N-acetylaspartate areas, expected to have greater tumor activity.

Leishmaniasis is a devastating tropical disease with limited therapeutic options. Depending on recently reported active anti-leishmanial compounds, we designed and synthesized a series of click modifiable 1,2,3-triazole and thiosemicarbazone hybrids. Most of the synthesized compounds showed comparable to superior activity to a well-established anti-leishmanial drug miltefosine. Compounds 2 and 10a showed nanomolar IC50s against promastigotes of L. major (227.4 nM and 140.3 nM respectively, vs 7.8 μM for miltefosine). Their antiamastigote IC50s were 1.4 μM and 1 μM respectively, which are 6 and 8 times the activity of miltefosine (IC50 8.09 μM). Folic and folinic acids reversed the anti-leishmanial effects of compounds 2 and 10a and hence we anticipate they act via an anti-folate mechanism. They exhibited better safety profiles than that of miltefosine on VERO cell lines. Also they were relatively safe on experimental mice when administered via oral and parenteral routes. Docking experiments on PTR1 identified preferential binding interactions and docking scores. Finally, drug-likeness and ligand efficiency were assessed indicating that both 2 and 10a are promising hits and/or leads as anti-leishmanial chemotherapeutic agents.

A highly selective and sensitive fluorescence assay for kanamycin has been developed that depends on complementation of two splits of DNA aptamer. One DNA split was labeled with CuS nanoparticle and the other was decorated with biotin, which enabled coupling with streptavidin magnesphere paramagnetic particles (PMPs). Complementation of the two-aptamer splits happened only in the presence of kanamycin and the subsequent sandwich was separated via a magnet. The released Cu(II) was reduced to Cu(I) by sodium ascorbate and finally catalyzed the click reaction between fluorogenic 3-azido-7-hydroxycoumarin and propargyl alcohol to afford the corresponding fluorescent 1,4-disubstituted-1,2,3-triazole. The fluorescence signal produced (λex. = 365 nm, λem. = 470 nm) was dependent on kanamycin concentration. Fluorescence signal amplification was found to be in good linear relationship with the logarithm of kanamycin concentration in the range of 0.04-20 nM. Furthermore, the proposed assay showed a good reproducibility, high selectivity and low detection limits for kanamycin determination. In addition, the capability of the proposed method to detect kanamycin in biological samples with satisfactory results was demonstrated.

Click chemistry was used to synthesize a new series of thioquinazolinone molecules equipped with propargyl moiety,1,2,3-triazolyl and isoxazolyl rings. Our design was based on merging pharmacophores previously reported to exhibit COX-2 inhibitory activities to a thioquinazolinone-privileged scaffold. The synthesized compounds were subjected to in vitro cyclooxygenase COX-1/COX-2 and 15-LOX inhibition assays. Compounds 2c, 3b, 3h, 3j, and 3k showed COX-2 inhibition with IC50 (μM) 0.18, 0.19, 0.11, 0.16 and 0.17 respectively. These values were compared to celecoxib (IC50 0.05 μM), diclofenac (IC50 0.8 μM) and indomethacin (IC50 0.49 μM) reference drugs. They also showed 15-LOX inhibition with IC50 (μM) 6.21, 4.33, 7.62, 5.21 and 3.98 respectively. These values were compared with Zileuton (IC50 2.41 μM) and Meclofenamate sodium (IC50 5.64 μM) as positive controls. These compounds were further challenged by PMA-induced THP-1 differentiation assay where compounds 2c and 3j inhibited monocyte to macrophage differentiation efficiently with IC50 values of 4.78 μM and 5.63 μM, respectively, compared to that of diclofenac sodium (4.86 μM). On the other hand, 3h demonstrated a significantly increased potency compared to diclofenac in this assay (IC50 = 0.13 μM). The same compounds exhibited significant in vivo anti-inflammatory effect as indicated by the formalin-induced rat-paw edema test. Docking experiments of compounds 2c, 3b, 3h, 3j, and 3k into COX-2 binding pocket have been conducted, where strong binding interactions have been identified and effective overall docking scores have been recorded. Their drug-likeness has been assessed using Molinspiration, Molsoft and Pre-ADMET software products.